ES2850198T3 - Spirodiamine derivatives as aldosterone synthase inhibitors - Google Patents

Abstract

Compounds of formula (I) ** (See formula) ** in which R1, R2, R3 and R4 are independently selected from H, alkyl and cycloalkyl; or R1 and R2 together form -CH2-CH2-; R5 and R6 are independently selected from H or alkyl; A1 is -CH- or -N-; A2 is -C (O) -; R12 is heteroaryl or substituted heteroaryl, wherein substituted heteroaryl is substituted with one to three substituents independently selected from alkyl, cycloalkyl, haloalkyl, hydroxy, alkoxy, cyano, and halogen; R13 is halogen, cyano, alkoxy, or haloalkoxy; R15 is H, alkyl, cycloalkyl, or halogen; m is zero or 1; and R9 and R14 together form -CH2-, R10 and R11 together form -CH2-, n is 1 and p is zero; or R9 and R14 together form -CH2-CH2-, R10 and R11 together form -CH2-, n is 1 and p is 1 and R7 and R8 are independently selected from H or alkyl; or R7 and R14 together form -CH2-, R8 and R11 together form -CH2-CH2-, n is 1, p is 1 and R9 and R10 are independently selected from H or alkyl; and pharmaceutically acceptable salts thereof.

Description

DESCRIPTION

Spirodiamine derivatives as aldosterone synthase inhibitors

The present invention relates to organic compounds useful for treatment or prophylaxis in a mammal, and in particular to aldosterone synthase inhibitors for the treatment or prophylaxis of chronic renal failure, congestive heart failure, hypertension, primary hyperaldosteronism and Cushing's syndrome.

The present invention provides novel compounds of formula (I)

in which

R1, R2, R3, and R4 are independently selected from H, alkyl, and cycloalkyl;

or R1 and R2 together form -CH2-CH2-;

R5 and R6 are independently selected from H or alkyl;

A1 is -CH- or -N-;

A2 is -C (O) -;

R12 is heteroaryl or substituted heteroaryl, wherein substituted heteroaryl is substituted with one to three substituents independently selected from alkyl, cycloalkyl, haloalkyl, hydroxy, alkoxy, cyano, and halogen;

R13 is halogen, cyano, alkoxy, or haloalkoxy;

R15 is H, alkyl, cycloalkyl, or halogen;

m is zero or 1; and

R9 and R14 together form -CH2-, R10 and R11 together form -CH2-, n is 1 and p is zero; or

R9 and R14 together form -CH2-CH2-, R10 and R11 together form -CH2-, n is 1 and p is 1 and R7 and R8 are independently selected from H or alkyl; or

R11 conjuntamente forman -CH2-CH2-, n es 1, p es 1 y R9 independientemente seleccionados de H o alquilo;R7 and R14 together form -CH2-,

R11 together form -CH2-CH2-, n is 1, p is 1 and R9 independently selected from H or alkyl;

and pharmaceutically acceptable salts thereof.

US2013 / 143863A1 discloses aldosterone synthase inhibitors (CYP11B2 or CYP11B1).

Described herein are aldosterone synthase inhibitors that have the potential to protect against organ / tissue damage caused by an absolute or relative excess of aldosterone. Hypertension affects approximately 20% of the adult population in developed countries. In people 60 years of age and older, this percentage increases to above 60%. Hypertensive subjects have an increased risk of other physiological complications including stroke, myocardial infarction, atrial fibrillation, heart failure, peripheral vascular disease, and renal dysfunction. The renin-angiotensin-aldosterone system is a pathway that has been associated with hypertension, blood volume, and saline balance and more recently with directly contributing to specific organ damage in advanced stages of heart failure or kidney failure. ACE inhibitors and angiotensin receptor blockers (ARBs) are used successfully to improve the length and quality of life of patients. patients. These drugs are not providing maximum protection. In a relatively large number of patients, RCTs and ARBs give rise to so-called aldosterone leakage, a phenomenon where aldosterone levels, after a first initial drop, return to pathological levels. It has been shown that the detrimental consequences of inappropriate increases in aldosterone levels (relative to salt levels / intake) can be minimized by aldosterone blockade with mineralocorticoid receptor antagonists. A direct inhibition of aldosterone synthesis is expected to provide even better protection as it will also further reduce the non-genomic effects of aldosterone.

The effects of aldosterone on Na / K transport result in increased sodium and water reabsorption and potassium secretion in the kidneys. In general, this results in an increase in blood volume and, therefore, an increase in blood pressure. Aside from its role in regulating renal sodium reabsorption, aldosterone can have deleterious effects on the kidney, heart, and vascular system, especially in a "high sodium" setting. It has been shown that under these conditions, aldosterone leads to an increase in oxidative stress that can ultimately contribute to organ damage. The infusion of aldosterone in rats with renal involvement (by treatment with high salt content or by unilateral nephrectomy) induces a wide variety of lesions in the kidney including glomerular expansion, podocyte lesion, interstitial inflammation, proliferation of mesangial cells and fibrosis reflected by proteinuria. More specifically, aldosterone was shown to increase the expression of the adhesion molecule ICAM-1 in the kidney. ICAM-1 is critically involved in glomerular inflammation. Similarly, aldosterone was shown to increase the expression of inflammatory cytokines, such as interleukin IL-1b and IL-6, MCP-1, and osteopontin. At the cellular level, it was shown that in vascular fibroblasts, aldosterone increased the expression of type I collagen mRNA, a mediator of fibrosis. Aldosterone also stimulates the accumulation of type IV collagen in rat mesangial cells and induces the expression of plasminogen activator inhibitor 1 (PAI-1) in smooth muscle cells. In summary, aldosterone has been revealed as a key hormone involved in kidney damage. Aldosterone plays an equally important role in mediating cardiovascular risk.

There is extensive preclinical evidence that MRI antagonists (spironolactone and eplerenone) improve blood pressure and cardiac and renal function in various preclinical models.

More recently, preclinical studies highlight the important contribution of CYP11B2 to cardiovascular and renal morbidity and mortality. The CYP11B2 inhibitor FAD286 and the MR antagonist spironolactone were evaluated in a rat model of chronic renal failure (high angiotensin II exposure, high salt content and uninephrectomy). Angiotensin II and high-salt treatment caused albuminuria, azotemia, renovascular hypertrophy, glomerular injury, increased PAI-1 and expression of osteopontin mRNA, as well as tubulointerstitial fibrosis.

Both drugs prevented these renal effects and attenuated hypertrophy of the aortic and cardiac media. After 4 weeks of treatment with FAD286, plasma aldosterone decreased, while spironolactone increased aldosterone at 4 and 8 weeks of treatment. Similarly, only spironolactone, but not FAD286, enhanced the expression of angiotensin II and salt-stimulated PAI-1 mRNA in the aorta and heart. In other studies, the CYP11B2 inhibitor FAD286 improved blood pressure and cardiovascular function and structure in rats with experimental heart failure. In the same studies, FAD286 was shown to improve kidney function and morphology.

Administration of an orally active CYP11B2 inhibitor, LCI699, to patients with primary hyperaldosteronism, leads to the conclusion that it effectively inhibits CYP11B2 in patients with primary hyperaldosteronism resulting in significantly lower surrounding aldosterone levels that corrected hypokalemia and blood pressure decreased slightly. Effects on the glucocorticoid axis were consistent with poor compound selectivity and latent inhibition of cortisol synthesis. Taken together, these data support the concept that a CYP11B2 inhibitor can reduce inappropriately high aldosterone levels. Achieving good selectivity against CYP11B1 is important for freedom from unwanted side effects on the HHS axis and will differentiate between different CYP11B2 inhibitors.

The compounds of the present invention according to formula (I) are potent inhibitors of CYPB11B2 and exhibit an improvement in selectivity towards CYP11B2 over CYP11B1, combined with an improvement in metabolic stability.

The objectives of the present invention are the compounds of formula (I) and their salts and esters mentioned above and their use as therapeutically active substances, a process for the manufacture of said compounds, intermediates, pharmaceutical compositions, drugs containing said compounds, their pharmaceutically acceptable salts or esters, the use of said compounds, salts or esters for the treatment or prophylaxis of diseases, especially in the treatment or prophylaxis of chronic renal failure, congestive heart failure, hypertension, primary hyperaldosteronism and Cushing's syndrome and the use of said compounds, salts or esters for the production of medicaments for the treatment or prophylaxis of chronic renal failure, congestive heart failure, hypertension, primary hyperaldosteronism and Cushing's syndrome.

The term "alkoxy" indicates a group of formula -O-R ', where R' is an alkyl group. Examples of the alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particular alkoxy group includes methoxy.

The term "alkyl" denotes a monovalent branched or linear saturated hydrocarbon group of 1 to 12 carbon atoms. In particular embodiments, the alkyl has 1 to 7 carbon atoms, and in more particular embodiments, 1 to 4 carbon atoms. Examples of alkyl include methyl, ethyl, propyl, and isopropyl, n-butyl, isobutyl, sec-butyl, and Particular alkyl groups include methyl, ethyl, and isopropyl.

The term "aryl" indicates a monovalent aromatic carbocyclic mono or bicyclic ring system comprising 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl. The particular aryl group is phenyl.

The term "cyano" indicates a -C eN group.

The term "cycloalkyl" indicates a monovalent saturated monocyclic hydrocarbon group of 3 to 10 ring carbon atoms. In particular embodiments, cycloalkyl indicates a monovalent saturated monocyclic hydrocarbon group with 3 to 8 ring carbon atoms. Examples of cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl, or cycloheptyl. A particular cycloalkyl group is cyclopropyl.

The term "haloalkoxy" indicates an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group has been replaced by the same or different halogen atoms. The term "perhaloalkoxy" indicates an alkoxy group where all the hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms. Examples of haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy, and pentafluoroethoxy.

The terms "halogen" and "halo" are used interchangeably herein and indicate fluorine, chlorine, bromine, or iodine. The particular halogens are chlorine and fluorine. One particular halogen is fluorine.

The term "heteroaryl" indicates a monovalent aromatic heterocyclic mono or bicyclic ring system of 5 to 12 ring atoms, comprising 1,2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of heteroaryl include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, benzinyl, diazepinyl, isoxazolyl, isoxazolyl, diazepinyl, isoxazolyl isoxazolyl. , isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl. Particular heteroaryl are imidazolyl, oxazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, isoxazolyl. Particular heteroaryl is and pyrazolyl.

The term "hydroxy" indicates an -OH group.

The term "pharmaceutically acceptable salts" refers to salts that maintain the biological efficacy and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid. , maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine and the like. Furthermore, these salts can be prepared by adding an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine resins, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine, and the like. Particular pharmaceutically acceptable salts of compounds of formula (I) are the hydrochloride salts, methanesulfonic acid salts and citric acid salts.

"Pharmaceutically acceptable esters" means that the compounds of general formula (I) can be modified into functional groups to provide derivatives that can be converted back to the parent compounds in vivo. Examples of such compounds include derivatives of physiologically acceptable and metabolically labile esters, such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters.

The term "protecting group" (GP) indicates the group that selectively blocks a reactive site on a multifunctional compound so that a chemical reaction can be carried out selectively at another deprotected reactive site in the sense conventionally associated with it in synthetic chemistry. Protecting groups can be removed at the appropriate time. Exemplary protecting groups are amino protecting groups, carboxy protecting groups, or hydroxy protecting groups. Particular protecting groups are tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), and benzyl (Bn). Other particular protecting groups are tert-butoxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). A more particular protecting group is tert- butoxycarbonyl (Boc).

The abbreviation uM stands for micromolar and is equivalent to the symbol | jM.

The compounds of the present invention may also contain unnatural ratios of atomic isotopes at one or more of the atoms that make up said compounds. For example, the present invention also encompasses isotopically-labeled variants of the present invention that are identical to those cited herein, except that one or more atoms are replaced by an atom having the different atomic mass or mass number. of the atomic mass or predominant mass number normally found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H ("D"), 3H ("T"), 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I and 125I. Certain isotopically-labeled compounds of the present invention (eg, those labeled with 3H or 14C) are useful in compound and / or substrate tissue distribution assays. Tritium (3H) and carbon 14 (14C) isotopes are useful for their ease of preparation and detectability. Additional substitution with heavier isotopes, such as deuterium (ie, 2H), may provide certain therapeutic benefits resulting from increased metabolic stability (eg, increased in vivo half-life or reduced dosage requirements), and therefore it may be preferred in some circumstances. Positron-emitting isotopes such as 15O, 13N, 11C, and 18F are useful for positron emission tomography (PET) studies to examine receptor occupancy by substrate. The isotopically-labeled compounds of the present invention can be prepared in general by the following procedures analogous to those disclosed in the schemes and / or examples herein below, substituting an isotopically-labeled reagent for a non-isotopically labeled reagent. In particular, compounds of formula (I) in which one or more H atoms have been replaced by a 2H atom are also an embodiment of the present invention.

The compounds of formula (I) may contain various asymmetric centers and may be present in the form of optically pure enantiomers, mixtures of enantiomers, such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates. .

According to the Cahn-Ingold-Prelog convention, the asymmetric carbon atom can have the "R" or "S" configuration.

Also an embodiment of the present invention are compounds according to formula (I) as described herein and pharmaceutically acceptable salts or esters thereof, in particular compounds according to formula (I) as described herein and pharmaceutically acceptable salts thereof, more particularly compounds according to formula (I) as described herein.

Also an embodiment of the present invention are compounds according to formula (I) as described herein in which R1 and R2 are alkyl or R1 and R2 together form -CH2-CH2-.

A particular embodiment of the present invention are compounds according to formula (I) as described herein, in which R1 and R2 are alkyl.

Another embodiment of the present invention are compounds according to formula (I) as described herein, in which R3 and R4 are H.

Also an embodiment of the present invention are compounds according to formula (I) as described herein, in which R13 is halogen.

Another embodiment of the present invention are compounds according to formula (I) as described herein, in which R15 is H.

Another particular embodiment of the present invention are compounds according to formula (I) as described herein, in which A1 is -CH-.

Also a particular embodiment of the present invention are compounds according to formula (I) as described herein, in which A2 is -C (O) -.

Another embodiment of the present invention are compounds according to formula (I) as described herein, in which R9 and R14 together form -CH2-, R10 and R11 together form -CH2-, n is 1 and p is zero.

Another particular embodiment of the present invention are compounds according to formula (I) as described described herein, wherein the heteroaryl group of R12 is selected from imidazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, and pyrimidinyl.

Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R12 is alkyl substituted pyrazolyl or alkyl substituted pyridinyl.

A particular embodiment of the present invention are compounds according to formula (I) as described herein, in which R12 is pyrazolyl substituted by alkyl.

Particular examples of compounds of formula (I) as described herein are selected from

5-chloro-3,3-dimethyl-2- [5- [2- (1-methylpyrazole-4-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] isoi ndolin-1-one;

5-chloro-2- [5- [2- (1-ethylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -3,3-dimethyl-isoindolin- 1-one;

5-chloro-2- [5- [2- (1-isopropylpyrazole-4-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] -3,3-dimethyl- isoi ndolin-1-one; 5-chloro-3,3-dimethyl-2- [5- [2- (1-methylimidazole-2-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1 -one;

5-chloro-3,3-dimethyl-2- [5- [2- (2-methylpyrazole-3-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] isoi ndolin-1-one;

5-chloro-3,3-dimethyl-2- [5- [2- (3-methylimidazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1 -one;

5-chloro-3,3-dimethyl-2- [5- [2- (4-methylpyridine-3-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1 -one;

3.3- dimethyl-2- [5- [2- (1-methylpyrazole-4-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pi ridyl] -1 -oxo-isoindolin- 5-carbonitrile; 2- [5- [2- (1-Ethylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -3,3-dimethyl-1-oxo-isoindoline- 5-carbonitrile; 2- [5- [2- (1-isopropylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -3,3-dimethyl-1-oxo-isoindoline- 5-carbonitrile;

3.3- dimethyl-2- [5- [2- (1-methylimidazole-2-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -1-oxo-isoindolin-5- carbonitrile; 3.3- dimethyl-2- [5- [2- (2-methylpyrazole-3-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] -1 -oxo-isoindolin- 5-carbonitrile; 3.3- dimethyl-2- [5- [2- (3-methylimidazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -1-oxo-isoindolin-5- carbonitrile; 3.3- dimethyl-2- [5- [2- (4-methylpyridine-3-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -1-oxo-isoindolin-5- carbonitrile; 2-methoxy-7,7-dimethyl-6- [5- [2- (1-methylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] pyrrolo [3 , 4-b] pyridin-5-one;

2-methoxy-7,7-dimethyl-6- [5- [2- (4-methylpyridine-3-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] pyrrolo [3 , 4-b] pi ridin-5-one;

2-methoxy-7,7-dimethyl-6- [5- [2- (2-methylpyrazole-3-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] pyrrolo [3 , 4-b] pyridin-5-one;

5-chloro-3-methyl-2- [5- [2- (1-methylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1-one ;

5'-chloro-2 '- [5- [2- (1-methylpyrazole-4-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] spiro [cyclopropane-1, 3'-isoindolin] -1'-one;

5'-chloro-2 '- [5- [2- (4-methylpyridine-3-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] spiro [cyclopropane-1, 3'-isoindolin] -1'-one;

5'-chloro-2 '- [5- [2- (2-methylpyrazole-3-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] spiro [cyclopropane-1, 3'-isoindolin] -1'-one;

(3R or 3S) -5-chloro-3-methyl-2- [5- [2- (1-methylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl ] isoindolin-1-one; (3S or 3R) -5-chloro-3-methyl-2- [5- [2- (1-methylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl ] isoindolin-1-one; 5-chloro-2- [5- [2- (4-methoxypyridine-3-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -3,3-dimethyl-isoindolin- 1-one; 5-doro-2- [5- [2- (3,6-dimethylpyrazine-2-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] -3,3- dimethyl-isoindolin-1-one; 5-doro-2- [5- [2- (1,5-dimethylpyrazole-4-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] -3,3- dimethyl-isoindolin-1-one; 5-doro-3,3-dimethyl-2- [5- [2- (3-methylisoxazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1 -one;

5-doro-3,3-dimethyl-2- [5- [2- (6-methylpirazine-2-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] isoi ndolin-1-one;

5-doro-3,3-dimethyl-2- [5- [2- (4-methylpyrimidine-5-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1 -one;

5-doro-3,3-dimethyl-2- [5- [2- (5-methylpirazine-2-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] isoi ndolin-1-one;

5-doro-2- [5- [2- (2,5-dimethylpyrazole-3-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] -3,3- dimethyl-isoindolin-1-one; 5-doro-3,3-dimethyl-2- [5- [2- (5-methyloxazole-4-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] isoi ndolin-1-one;

5-doro-3,3-dimethyl-2- [5- [2- (pi rimidine-2-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1- ona;

5-doro-3,3-dimethyl-2- [5- [2- (5-methylpyrimidine-2-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1 -one;

5-doro-2- [5- [2- [3- (difluoromethyl) -1-methyl-pyrazole-4-carbonyl] -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] - 3,3-dimethylisoindolin-1-one;

5- [6- [5- (6-doro-1,1-dimethyl-3-oxo-isoindolin-2-yl) -3-pyridyl] -2,6-diazaspiro [3.3] heptane-2-carbonyl] pyridine -3-carbonitrile; 5-doro-2- [5- [2- (3-methoxypyrazine-2-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -3,3-dimethyl-isoindolin- 1-one; 5-doro-3,3-dimethyl-2- [5- [2- (pyrazine-2-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1- ona;

5-doro-3,3-dimethyl-2- [5- [2- (5-methylisoxazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1 -one;

5-doro-3,3-dimethyl-2- [5- [2- (pi rimidine-5-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1- ona;

5-doro-3,3-dimethyl-2- [5- [2- (4-methyloxazole-5-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] isoi ndolin-1-one;

5-doro-3,3-dimethyl-2- [5- [2- (oxazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1-one ;

5-doro-3,3-dimethyl-2- [5- [2- (2-methyloxazole-5-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] isoi ndolin-1-one;

5-doro-2- [5- [2- (2,4-dimethyloxazole-5-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] -3,3- dimethyl-isoindolin-1-one; 5-doro-3,3-dimethyl-2- [5- [2- (2-methyloxazole-4-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] isoi ndolin-1-one;

2- [6- [5- (6-doro-1,1-dimethyl-3-oxo-isoindolin-2-yl) -3-pyridyl] -2,6-diazaspiro [3.3] heptane-2-carbonyl] pyridine -3-carbonitrile; 5-doro-2- [5- [2- (5-doro-2-methyl-pyrimidine-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -3, 3-dimethyl-isoindolin-1-one;

5-doro-2- [5- [2- (4,6-dimethylpyrimidine-5-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] -3,3-dimethyl -isoindolin-1-one; 5- doro-2- [5- [2- (2,4-dimethylpyridine-3-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -3,3-dimethyl- isoindolin-1-one; 3- [6- [5- (6-doro-1,1-dimethyl-3-oxo-isoindolin-2-yl) -3-pyridyl] -2,6-diazaspiro [3.3] heptane-2-carbonyl] pyridine -4-carbonitrile; (3S or 3R) -5-doro-2- [5- [2- (1-ethylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -3- methyl-isoindolin-1-one; (3R or 3S) -5-doro-2- [5- [2- (1-ethylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -3- methyl-isoindolin-1-one; 6- chloro-2- [5- [2- (1-methylpirazol-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -3,4-dihydroisoquinolin-1 -one; (3R or 3S) -5-doro-3-methyl-2- [4-methyl-5- [2- (1-methylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1-one;

(3S or 3R) -5-doro-3-methyl-2- [4-methyl-5- [2- (1-methylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1-one;

5-doro-3,3-dimethyl-2- [5- [7- (1-methylpyrazole-4-carbonyl) -2,7-diazaspi ro [3.5] nonan-2-yl] -3-pyridyl] isoindolin- 1-one;

5-doro-3,3-dimethyl-2- [5- [7- (4-methylpyridine-3-carbonyl) -2,7-diazaspiro [3.5] nonan-2-yl] -3-pyridyl] isoindolin-1 -one;

5-doro-2- [5- [7- (1-ethylpyrazole-4-carbonyl) -2,7-diazaspiro [3.5] nonan-2-yl] -3-pyridyl] -3,3-dimethyl-isoindolin- 1-one;

5-doro-3,3-dimethyl-2- [5- [2- (1-methylpyrazole-4-carbonyl) -2,7-diazaspi ro [3.5] nonan-7-yl] -3-pyridyl] isoindolin- 1-one;

5-doro-2- [5- [2- (1-ethylpyrazole-4-carbonyl) -2,7-diazaspiro [3.5] nonan-7-yl] -3-pyridyl] -3,3-dimethyl-isoindolin- 1-one;

5-doro-3,3-dimethyl-2- [5- [2- (4-methylpyridine-3-carbonyl) -2,7-diazaspiro [3.5] nonan-7-yl] -3-pyridyl] isoindolin-1 -one; and and pharmaceutically acceptable salts thereof.

Other particular examples of compounds of formula (I) as described herein are selected from

5-chloro-3,3-dimethyl-2- [5- [2- (1-methylpyrazole-4-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] isoi ndolin-1-one;

5-chloro-2- [5- [2- (1-ethylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -3,3-dimethyl-isoindolin- 1-one;

5-chloro-3,3-dimethyl-2- [5- [2- (4-methylpyridine-3-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1 -one;

2- [5- [2- (1-Ethylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -3,3-dimethyl-1-oxo-isoindoline- 5-carbonitrile; 2-methoxy-7,7-dimethyl-6- [5- [2- (1-methylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] pyrrolo [3 , 4-b] pyridin-5-one;

5'-chloro-2 '- [5- [2- (1-methylpyrazole-4-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] spiro [cyclopropane-1, 3'-isoindolin] -1'-one;

5-chloro-3,3-dimethyl-2- [5- [7- (1-methylpyrazole-4-carbonyl) -2,7-diazaspi ro [3.5] nonan-2-yl] -3-pyridyl] isoindolin- 1-one;

5-chloro-2- [5- [7- (1-ethylpyrazole-4-carbonyl) -2,7-diazaspiro [3.5] nonan-2-yl] -3-pyridyl] -3,3-dimethyl-isoindolin- 1-one;

5-chloro-3,3-dimethyl-2- [5- [2- (1-methylpyrazole-4-carbonyl) -2,7-diazaspi ro [3.5] nonan-7-yl] -3-pyridyl] isoindolin- 1-one;

and pharmaceutically acceptable salts thereof.

Processes for the manufacture of compounds of formula (I) as described herein are an object of the invention.

The preparation of compounds of formula (I) of the present invention can be carried out in sequential or convergent synthetic routes. The syntheses of the invention are shown in the following general schemes. The skills required to carry out the reaction and purification of the resulting products are known to those of skill in the art. In the event that a mixture of enantiomers or diastereoisomers occurs during a reaction, these enantiomers or diastereoisomers can be separated by procedures described herein or known to those skilled in the art such as, for example, chiral chromatography or crystallization. The substituents and indices used in the following description of the procedures have the meaning given herein.

The following abbreviations are used in this text:

AcOH = acetic acid, BOC = t-butyloxycarbonyl, BuLi = butyllithium, CDI = 1,1-carbonyldiimidazole, DCM = dichloromethane, DBU = 2,3,4,6,7,8,9,10-octahydro-pyrimido [1 , 2-a] acetin, DCE = 1,2-dichloroethane, DIBALH = di-Z-butylaluminum hydride, DCC = N, N-dicyclohexylcarbodiimide, DMA = N, N'-dimethylacetamide, DMAP = 4- dimethylaminopyridine, DMF = W, W'-dimethylformamide, EDCI = N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, EtOAc = ethyl acetate, EtOH = ethanol, Et2O = diethyl ether, Et3N = triethylamine, eq = equivalents , HATU = O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate, HPLC = high performance liquid chromatography, HOBT = 1-hydroxybenzotriazole, Huenig base = iP ^ NEt = W-ethyldiisopropylamine, IPC = control during the process, LAH = lithium aluminum hydride, LDA = lithium diisopropylamide, LiBH4 = lithium borohydride, MeOH = methanol, NaBH3CN, sodium cyanoborohydride, NaBH4 = sodium borohydride, Nal = iodide sodium, Red-Al = sodium bis (2-methoxyethoxy) aluminum hydride, TA = room temperature, TBDMSCl = t-butyldimethylsilyl chloride, TFA = trifluoroacetic acid, THF = tetrahydrofuran, quantitative = quantitative.

The pyridine compounds substituted with halogen or triflate, preferably iodine, 2 or 8 , react with arylactams 1 in solvents such as 1,4-dioxane, in the presence of copper (I) iodide, potassium or cesium carbonate or potassium phosphate, a chelating 1,2-diamino compound such as N, W-dimethylethylenediamine or trans-1,2-diaminocyclohexane or a chelating beta-ketoester compound such as 2-isobutyryl-cyclohexanone, at elevated temperatures, optionally with the aid of microwave heating to form lactam substituted heterocyclic compounds 3 and 5 as described in Scheme 1a and Scheme 1b (step a). The 4 or 6 amino compounds (compounds that are known or can be readily prepared by procedures known in the art) react with the 3 substituted pyridine compounds under similar conditions as used in step a (step b), or preferably using the 'Buchwald' conditions, for example, using catalysts like Pd (OAc) 2 and chelating ligands like Xanphos in the presence of a base like t-BuONa in solvents like dioxane at elevated temperature to give compounds 5 or 7 . Compounds 5 with R101 being a protecting group, for example the Boc group, can then be converted to compounds 7 by removal of the protecting group R101 and reaction with a suitable activated carboxyl or sulfonyl compound (steps c, d; schemes 1a and 1b).

Scheme 1a

R101 is a suitable protecting group

Scheme 1b

X is halogen or OSO2CF3

R101 is a suitable protecting group or A2-R12

The carbamates 101 (scheme 2a) react with poly (phosphoric acid) at elevated temperature (eg, 100-180 ° C) to form the lactam derivatives 102 (step a). The trifluoroacetamides 103 can be cyclized into the 2,2,2-trifluoroethanone compounds 104 by treatment with paraformaldehyde in a mixture of concentrated sulfuric acid and acetic acid preferably around room temperature (step b). Removal of the trifluoroactyl group by treatment with, for example, potassium hydroxide in a solvent such as ethanol at temperatures around room temperature gives the secondary amino compounds 105 (step c). Oxidation of the secondary amino compounds 105 , for example, with iodine benzene and potassium bromide preferably in water gives the lactam compounds 102 (step d). Reaction of compounds 106 (scheme 2b) with a Grignard reagent R1MgX in a solvent such as THF preferably around 0 ° C gives adducts 107 (step e). Post-treatment with triethylsilane and boron trifluoride etherate in a solvent such as dichloromethane and in a temperature range preferably between -25 ° C and RT gives compounds 108 (step f). Introduction of a methoxybenzyl protecting group into compounds 109 (for example, by treatment with sodium bis (trimethylsilyl) amide and 1-bromomethyl-4- methoxybenzene in THF between 0 ° C and RT) gives protected compounds 110 (step g); Similarly, a methoxybenzyl protecting group can be introduced into compounds 108 . Alternatively, compounds 110 can be obtained from halomethyl compounds 115 by reaction with p-methoxybenzylamine in solvents like THF around RT (step m). Treatment of compounds 108 bearing an additional methoxybenzyl protecting group or compounds 110 with a base such as sodium hydride in a solvent such as THF and then with an alkyl halide, mesylate or tosylate preferably between RT and the reflux temperature of the solvent gives compounds 111 with one or both groups R1 and R2 other than hydrogen (step h). Alternatively, treating compounds 108 bearing an additional methoxybenzyl protecting group or compounds 110 with a base such as NaH, LDA, or LiHMDS in solvents such as DMF, tetrahydrofuran, or 1,2-dimethoxyethane and then with one or sequentially with two different alkyl halides, mesylates or tosylates preferably between -78 ° C and the reflux temperature of the solvents give compounds 111 with structurally different or structurally identical R1 and R2 groups (step h). Removal of the protecting group, for example, by treatment with trifluoroacetic acid at elevated temperature gives compounds 112 (step i). Treatment of compounds 110 with a base such as sodium hydride in a solvent such as THF and then with an alpha, omega di-haloethane, for example 1,2-dibromoethane, preferably between RT and the reflux temperature of the solvent gives the compounds spiro 113 (step k) and after subsequent removal of the protecting group, the spiro 114 compounds (stage 1).

Alternatively, (scheme 2c), compounds 117 where R1 and R2 are alkyl groups can be obtained from cyano compounds 116 and suitable Grignard reagents, by adding two different reagents sequentially or a single Grignard reagent in excess. (to obtain compounds with identical R1 and R2) preferably in the presence of fephra-titanium isopropoxide in solvents such as THF preferably in a temperature range between 0 ° C and RT (step n). Compounds 117 where R1 = H and R2 are an alkyl group can be obtained from cyano compounds 116 and suitable Grignard reagents in solvents such as THF preferably in a temperature range between 0 ° C and RT (step n) followed reduction of the imine formed with sodium borohydride in, for example, methanol around RT (step n). Compounds 119 are obtained from compounds 117 by reacting first with ethylmagnesium bromide and fephra-titanium isopropoxide in solvents such as THF preferably in a temperature range between -78 ° C and RT followed by treatment with BF3- Et2O (step p). Compounds 117 and 119 are subjected to ring closure by reaction with catalysts such as dichloro [1,1'-jb / s (diphenylphosphino) -ferrocene] palladium (II) in solvents such as DMF in the presence of a base such as iPr2NEt preferably in a temperature range from about 100 ° C to 150 ° C in an autoclave in the presence of carbon monoxide to form compounds 118 and 120 (step o).

Scheme 2a

Scheme 2b

X is halogen or OSO2CF3

R is alkyl

Scheme 2c

X is halogen or OSO2CF3

Halogen or triflate substituted compounds 8 can be prepared by reacting amino compounds 4 with substituted di-halo or di-triflate pyridines 2 using conditions as described in Schemes 1 (step a), (Scheme 3).

Scheme 3

R101 is a suitable protecting group or A2-R12

Also an embodiment of the present invention is a process for preparing a compound of formula (I) as defined above which comprises

a) the reaction of a compound of formula (II) in the presence of a compound of formula (III);

or

b) reacting a compound of formula (IV) in the presence of a compound of formula (V);

R10, R11, R12, R13, R14, son como se describe en el presente documento y X en la etapa a) es halógeno o triflato y es halógeno en la etapa b).in which

R10, R11, R12, R13, R14, are as described herein and X in step a) is halogen or triflate and is halogen in step b).

In particular, in step a), in the presence of copper (I) iodide, potassium or cesium carbonate or potassium phosphate, a 1,2-diamino chelating compound such as W, W-dimethylethylenediamine or trans-1,2 -diamino-cyclohexane or a chelating beta-ketoester compound such as 2-isobutyryl-cyclohexanone, at elevated temperatures, preferably with the aid of microwave heating and in solvents such as 1,4-dioxane.

In particular, in step b), in the presence of a base, such as triethylamine, in a solvent such as dichloromethane at a temperature between -10 ° C and RT.

Also an object of the present invention is a compound according to formula (I) as described herein for use as a therapeutically active substance.

Also, an object of the present invention is a pharmaceutical composition comprising a compound according to formula (I) as described herein and a therapeutically inert carrier.

The present invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of chronic renal failure, congestive heart failure, hypertension, primary hyperaldosteronism and Cushing's syndrome.

The present invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of diabetic nephropathy.

The present invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of renal or cardiac fibrosis.

The present invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of chronic renal failure.

The present invention also relates to the use of a compound according to formula (I) as described in

herein for the treatment or prophylaxis of congestive heart failure.

The present invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of hypertension.

The present invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of primary hyperaldosteronism.

A particular embodiment of the present invention is a compound according to formula (I) as described herein for the treatment or prophylaxis of chronic renal failure, congestive heart failure, hypertension, primary hyperaldosteronism and Cushing's syndrome.

Also a particular embodiment of the present invention is a compound according to formula (I) as described herein for the treatment or prophylaxis of diabetic nephropathy.

Another particular embodiment of the present invention is a compound according to formula (I) as described herein for the treatment or prophylaxis of renal or cardiac fibrosis.

Also a particular embodiment of the present invention is a compound according to formula (I) as described herein for the treatment or prophylaxis of chronic renal failure.

Also a particular embodiment of the present invention is a compound according to formula (I) as described herein for the treatment or prophylaxis of congestive heart failure. Also a particular embodiment of the present invention is a compound according to formula (I) as described herein for the treatment or prophylaxis of hypertension.

Also a particular embodiment of the present invention is a compound according to formula (I) as described herein for the treatment or prophylaxis of primary hyperaldosteronism.

The present invention also relates to the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of chronic renal failure, congestive heart failure, hypertension, primary hyperaldosteronism and Cushing's syndrome.

The present invention also relates to the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of diabetic nephropathy.

The present invention also relates to the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of renal or cardiac fibrosis.

Also an embodiment of the present invention is the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of chronic renal failure.

Also an embodiment of the present invention is the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of congestive heart failure.

Also an embodiment of the present invention is the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of hypertension.

Also an embodiment of the present invention is the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of primary hyperaldosteronism.

Test procedures

The present document identified the use of the G-402 cell line as a host cell to ectopically express (transiently or stably) CYP11 family enzymes. Specifically, stable G-402 cells were developed that ectopically express enzymatic activity of human CYP11B1, human CYP11B2, human CYP11A1, crab macaque CYP11B1, or crab macaque CYP11B2. Importantly, the identified G-402 cell line expresses cofactors (adrenodoxin and adrenodoxin reductase) important for CYP11 family activity and no relevant CYP11 family enzyme activity was detected (compared to H295R cells) in these cells. Therefore, the G-402 cell line is uniquely suitable as a host cell for the ectopic expression of CYP11 family enzymes.

G-402 cells can be obtained from ATCC (CRL-1440) and were originally derived from a renal leiomyoblastoma.

The expression plasmids contain the ORF for either CYP11B1 or CYP11B2 human / crabby macaque under the control of a suitable promoter (CMV promoter) and a suitable resistance marker (neomycin). Using standard techniques, the expression plasmid is transfected into G-402 cells and these cells are then selected to express the given resistance markers. The individual cell clones are then selected and evaluated for exhibiting the desired enzymatic activity using 11-deoxycorticosterone (Cyp11B2) or 11-deoxycortisol (Cyp11B1) as a substrate.

G-402 cells expressing CYP11 constructs were established as described above and maintained in McCoy's Modified 5a Medium, ATCC Catalog # 30-2007 containing 10% FCS and 400 µg / ml G418 ( Geneticin) at 37 ° C under an atmosphere of 5% CO2 / 95% air. Cellular enzymatic assays were performed in DMEM / F12 medium containing 2.5% carbon-treated FCS and appropriate concentration of substrate (11-deoxycorticosterone, 11-deoxycortisol or 0.3-10 uM corticosterone). To test for enzyme activity, cells were seeded in 96-well plates and incubated for 16 h. An aliquot of the supernatant is then transferred and analyzed to determine the concentration of the expected product (aldosterone for CYP11B2; cortisol for CYP11B1). The concentrations of these steroids can be determined using CisBio's HTRF assays analyzing either aldosterone or cortisol.

Inhibition of the release of the steroids produced can be used as a measure of the respective enzyme inhibition by the test compounds added during the cellular enzyme assay. Dose-dependent inhibition of enzyme activity by a compound is calculated by plotting added inhibitor concentrations (x-axes) versus measured product / steroid level (y-axes). Inhibition is then calculated by fitting the 4-parameter sigmoidal function (Morgan-Mercer-Flodin (MMF) model) to the raw data points using the least squares procedure:

where A is the maximum y-value, B is the EC50 factor determined using XLFit, C is the minimum y-value, and D is the slope value.

The maximum value A corresponds to the amount of steroid produced in the absence of an inhibitor, the value C corresponds to the amount of steroid detected when the enzyme is totally inhibited.

EC50 values for compounds claimed herein were tested with the described G402-based assay system. The enzymatic activity of Cyp11B2 was tested in the presence of 1 pM deoxycorticosterone and varying amounts of inhibitors; Cyp11B1 enzyme activity was tested in the presence of 1 pM deoxycortisol and varying amounts of inhibitors.

Compounds of formula (I) and their pharmaceutically acceptable salts or esters thereof as described herein have EC50 (CYP11B2) values between 0.000001 uM and 1000 uM, particular compounds have EC50 (CYP11B2) values. between 0.00005 uM and 500 uM, other particular compounds have EC50 values (CYP11B2) between 0.0005 uM and 50 uM, more particular compounds have EC50 values (CYP11B2) between 0.0005 uM and 5 uM. These results have been obtained using the enzymatic assay described.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (for example, in the form of pharmaceutical preparations). Pharmaceutical preparations can be administered internally, such as orally (for example, in the form of tablets, coated tablets, lozenges, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (for example, in the form of nasal sprays) or rectally (for example, in the form of suppositories). However, administration can also be effected parenterally, such as intramuscularly or intravenously (eg, in the form of injectable solutions).

The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert inorganic or organic adjuvants for the production of tablets, coated tablets, dragees and hard gelatin capsules. Lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts, etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.

Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.

Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

Suitable adjuvants for injectable solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

Suitable adjuvants for suppositories are, for example, natural or hydrogenated oils, waxes, fats, liquid or semi-solid polyols, etc.

In addition, the pharmaceutical preparations may contain preservatives, solubilizers, substances that increase viscosity, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain still other therapeutically valuable substances.

The dosage can vary within wide limits and will, of course, be adjusted to the individual requirements in each particular case. In general, in the case of oral administration, a daily dosage of about 0.1 mg to 20 mg per kg of body weight, preferably about 0.5 mg to 4 mg per kg of body weight (for example about 300 mg per person), preferably divided into 1-3 individual doses, which may consist, for example, of the same amounts. It will be clear, however, that the upper limit given in this document can be exceeded when shown to be indicated.

According to the invention, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis of aldosterone-mediated diseases.

The compounds of formula (I) or their pharmaceutically acceptable salts and esters herein are inhibitors of CYP11B2. The compounds of formula (I) or their pharmaceutically acceptable salts and esters herein also exhibit variable inhibition of CYP11B1 but exhibit an improvement in selectivity towards CYP11B2 over CYP11B1. Such compounds can be used for the treatment or prophylaxis of conditions exhibiting excessive cortisol production / levels or excessive levels of both cortisol and aldosterone (eg, Cushing's syndrome, burn trauma patients, depression, post-traumatic stress disorder, chronic stress, corticotrophic adenomas, Cushing's disease).

According to the invention, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis of cardiovascular conditions (including hypertension and heart failure), vascular conditions, endothelial dysfunction, baroreceptor dysfunction, kidney conditions, liver conditions, fibrotic diseases, inflammatory conditions, retinopathy, neuropathy (such as peripheral neuropathy), pain, insulinopathy, edema, edematous conditions, depression, and the like.

Cardiovascular conditions include congestive heart failure, coronary heart disease, arrhythmia, atrial fibrillation, cardiac injury, decreased ejection fraction, diastolic and systolic heart dysfunction, fibrinoid coronary artery necrosis, cardiac fibrosis, hypertrophic cardiomyopathy, impaired arterial compliance, impaired diastolic filling. , ischemia, left ventricular hypertrophy, myocardial and vascular fibrosis, myocardial infarction, myocardial necrotic lesions, cardiac arrhythmias, prevention of sudden cardiac death, restenosis, stroke, vascular damage.

Kidney conditions include acute and chronic renal failure, nephropathy, end-stage renal failure, diabetic nephropathy, decreased creatinine clearance, decreased glomerular filtration, reticulated mesangial matrix expansion with or without significant hypercellularity, focal glomerular capillary thrombosis, global fibrinoid necrosis, glomerulosclerosis, ischemic lesions, malignant nephrosclerosis (such as ischemic retraction, oligoalbuminuria, proteinuria, reduced renal blood flow, renal artery disease, swelling and proliferation of intracapillary (endothelial and mesangial) and / or extracapillary (crescent) cells.

Kidney conditions also include glomerulonephritis (such as diffuse proliferative, focal proliferative, mesangial proliferative, membranoproliferative, minimal change membranous glomerulonephritis), lupus nephritis, non-immune basement membrane abnormalities (such as Alport syndrome), renal fibrosis, and glomerulosclerosis. (such as global or nodular focal and segmental glomerulosclerosis).

Liver conditions include, but are not limited to, hepatic steatosis, nonalcoholic steatohepatitis, liver cirrhosis, liver ascites, liver congestion, and the like.

Vascular conditions include, but are not limited to, thrombotic vasculopathy (such as parietal fibrinoid necrosis, red blood cell extravasation and fragmentation, and luminal and / or parietal thrombosis), proliferative arteriopathy (such as inflamed myointimal cells surrounded by mucinous extracellular matrix and nodular thickening), atherosclerosis, n decreased vascular compliance (such as stiffness, reduction in ventricular compliance, and reduction in vascular compliance), endothelial dysfunction, and the like.

Inflammatory conditions include, but are not limited to, joint rheumatism (eg, osteoarthritis), inflammatory diseases of the airways (eg, chronic obstructive pulmonary disease (COPD)), and the like.

Pain includes, but is not limited to, acute pain, chronic pain (eg, arthralgia), and the like.

Edema includes, but is not limited to, peripheral tissue edema, hepatic congestion, hepatic ascites, splenic congestion, respiratory or pulmonary congestion, and the like.

The insulinopatías include, but are not limited to, insulin resistance, diabetes mellitus type I, diabetes mellitus type II, glucose sensitivity, pre - diabetic state, prediabetes, metabolic syndrome and the like.

Fibrotic diseases include, but are not limited to, myocardial and intrarenal fibrosis, renal interstitial fibrosis, and liver fibrosis.

In addition, the compounds of formula (I) or their pharmaceutically acceptable salts and esters as described herein can also be used for the treatment or prophylaxis of a cardiovascular condition selected from the group consisting of hypertension, heart failure (in particular, heart failure after myocardial infarction), left ventricular hypertrophy and stroke.

In another embodiment, the cardiovascular condition is hypertension.

In a particular embodiment, the cardiovascular condition is treatment-resistant hypertension.

In another embodiment, the cardiovascular condition is heart failure.

In another embodiment, the cardiovascular condition is left ventricular hypertrophy.

In another embodiment, the cardiovascular condition is congestive heart failure, more particularly in patients with preserved left ventricular ejection fraction.

In another embodiment, the cardiovascular condition is stroke.

In another embodiment, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis of kidney disease.

In another embodiment, the kidney condition is nephropathy.

In another embodiment, the kidney condition is autoimmune glomerulonephritis.

In another embodiment, the chronic renal failure is diabetic nephropathy.

In another embodiment, the fibrotic disease is renal or cardiac fibrosis.

In another embodiment, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis of type II diabetes mellitus.

In another embodiment, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis of type I diabetes mellitus.

In another embodiment, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis of diabetic retinopathy.

The invention is hereinafter illustrated by examples, which are not limiting. In case the preparative examples are obtained as a mixture of enantiomers, the pure enantiomers can be separated by procedures described herein or by procedures known to those skilled in the art, such as, for example, chiral chromatography or crystallization.

Examples

All examples and intermediates were prepared under argon atmosphere unless otherwise specified.

Intermediate A-1

6-chloro-3,4-dihydro-2H-isoq uinolin-1-one

[To [2- (3-chloro-phenyl-ethyl-1-carbamic acid

At 0 ° C, methyl chloroformate (4.6 g, 48 mmol) was added dropwise to a solution of 2- (3-chloro-phenyl) -ethylamine (5.0 g, 32 mmol) and Et3N (6 , 4 g, 64 mmol) in DCM (100 ml). After the addition, the mixture was stirred at room temperature for 0.5 hours. The organic layer was washed with water (3 x 30 mL), 1N HCl (20 mL), and brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. After drying in vacuo, the compound of titer (6.49 g, 95%) as a white solid. MS: 214.1 (M + H) +.

Under protection of N2, a mixture of [2- (3-doro-phenyl) -ethyl] -carbamic acid methyl ester (5.0 g, 23.4 mmol) and PPA (poly (phosphoric acid)) was vigorously stirred. (20 g) in a 250 ml round bottom flask at 120 ° C for 2 hours. After cooling to room temperature, the reaction mixture was treated with ice water and aqueous ammonia solution to adjust the pH to 8. The mixture was then extracted with EtOAc, and the organic layer was washed with brine, dried over Anhydrous Na2SO4 and filtered. After removal of the solvent under reduced pressure, the obtained crude product was further washed with ethyl ether to give the title compound (1.66 g, 39%) as a white solid. MS: 182.0 (M + H) +.

Intermediate A-2

5-chloro-3-methyl-2,3-dihydro-isoindol-1-one

To a stirred solution of 2-bromo-5-chlorobenzonitrile (80 g, 370 mmol) in THF (1000 ml) at 0 ° C was added MeMgBr (370 ml, 1110 mmol) dropwise. The reaction mixture was stirred at 0-5 ° C for 5 hours before MeOH (500 ml) was added dropwise. After the solution was stirred for another 15 min, NaBH4 (28 g, 740 mmol) was carefully added and the resulting mixture was stirred at room temperature for 16 hours. Then the reaction solution was poured into water, extracted with EtOAc (3x). The combined organic layers were dried over anh Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by flash chromatography on silica gel (petroleum ether: EtOAc = 3: 1) to give the compound of the titer (30 g, 35%) as a yellowish oil. MS: 235.5 (M + H) +.

A mixture of 1- (2-bromo-5-chlorophenyl) ethanamine (30 g, 127.9 mmol), Pd (dppf) Cl2 (3.2 g, 12.79 mmol) and DIPEA (49.5 g) was stirred. , 383.7 mmol) in DMF (1.2 L) in an autoclave under 2 MPa CO at 130 ° C for 24 hours. After After cooling to room temperature, the reaction mixture was diluted with EtOAc (500 mL). The organic layer was washed with brine, filtered and concentrated in vacuo to give a crude product which was purified by flash chromatography on silica gel (petroleum ether: EtOAc = 3: 1) to give the title compound (5, 2 g, 23%) as a brown solid. MS: 181.6 (M + H) +.

Intermediate A-3

5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one

To a stirred solution of 2-bromo-5-chloro-benzonitrile (10 g, 46 mmol) in THF (200 ml) at 0 ° C was added MeMgBr (77 ml, 230 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stir for 2 hours. Ti (Oi-Pr) 4 (13 g, 46 mmol) was added and the solution was stirred for another 16 hours before it was quenched with aq. of HCl and washed with EtOAc. The aqueous phase was adjusted to pH ~ 10 with aq. NaOH, and extracted with EtOAc (3x). The combined organic layers were concentrated to give a crude title product (3.8 g, 33%) as an oil, which was used directly in the next step without further purification. MS: 249.30 (M + H) +.

A mixture of 1- (2-bromo-5-chloro-phenyl) -1-methyl-ethylamine (3.8 g, 15.3 mmol), Pd (dppf) Cb (0.4 g, 0.55 mmol) and DIPEA (6 g, 45.9 mmol) in DMF (20 ml) in an autoclave under 2 MPa CO at 130 ° C for 16 hours. After it was cooled to room temperature, the reaction mixture was diluted with EtOAc (300 ml). The organic layer was washed with brine (80 ml x2), filtered and concentrated in vacuo to give a crude product which was purified by flash chromatography on silica gel to give the title compound (1.13 g, 38%) as a brown solid. MS: 195.70 (M + H +)

Intermediate A-4

3,3-dimetM-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrMo

To a solution of 4-bromo-2-methyl-benzoic acid (30.0 g, 0.14 mol) in 115 ml of methanol, thionyl chloride (20.25 ml, 0.28 mol) was added slowly and The reaction mixture was stirred at 70 ° C for 2 hours before being concentrated to give a crude product which was then purified by flash chromatography on silica gel to give the title compound (30.03 g, 93.6% ) as a solid.

A mixture of 4-bromo-2-methyl-benzoic acid methyl ester (26.0 g, 113.5 mmol) and CuCN (12.48 g, 140.7 mmol) was heated at 180 ° C for 5 hours before from being poured into ice water. The solid precipitate was collected by vacuum filtration to give a crude product which was then purified by flash chromatography on silica gel to give the title compound (12.53 g, 63%) as a solid.

[C1 2-Bromomethyl-4-kano-benzoic acid methyl ester

A mixture of 4-cyano-2-methyl-benzoic acid methyl ester (12.5 g, 71.35 mmol), NBS (12.7 g, 71.35 mmol) and dibenzoyl peroxide (BPO) ( 0.8 g, 3.28 mmol) in CCl4 (200 ml) at reflux for 3 hours. After it was cooled to room temperature, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give a crude product (18.2 g) which was used in the next step reaction without further purification.

[D12- (4-methoxy-benzyl) -1-oxo-2,3-dil'ihydro-1H-isoindole-5-carbonitrile

To a solution of 2-bromomethyl-4-cyano-benzoic acid methyl ester (18.1 g, 71.24 mmol) in THF (300 ml) was added PMBNH2 (23.4 g, 178.1 mmol) to 0 ° C and the reaction mixture was stirred at room temperature for 16 hours. After vacuum filtration, the filtrate was concentrated in vacuo. The obtained residue was redissolved in EtOAc and washed with water and brine. The organic layer was dried over anh Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by flash chromatography on silica gel (11.69 g, 56.0%) as a solid.

A solution of 2- (4-methoxy-benzyl) -1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile (11.6 g, 41.7 mmol) in THF (300 ml) was added NaH (8.34 g, 208.4 mmol, 60% in petroleum jelly) was added and the reaction mixture was stirred at room temperature for 1 hour before iodomethane (35.5 g, 250.1 mmol) was added . After the addition, the reaction mixture was stirred at 70 ° C for 2 hours until all the starting material was consumed. After it cooled down to room temperature, sat. ac. NH4Cl solution and the mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over anh MgSO4, filtered and concentrated under reduced pressure to give a crude product which was purified by flash chromatography on silica gel to give the title compound (7.22 g, 56.5% ) as a solid.

IF13,3-dimethyl-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile

To a solution of 2- (4-methoxy-benzyl) -3,3-dimethyl-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile (3.5 g, 11.42 mmol) in MeCN (70 ml) CAN (18.79 g, 34.27 mmol) was added in 30 ml of water at 0 ° C. The resulting reaction mixture was stirred at 0 ° C for 1 hour until all the starting material was consumed. The reaction mixture was extracted between water and EtOAc and the combined organic layers were dried over anh MgSO4, filtered and concentrated under reduced pressure to give a crude product which was purified by flash chromatography on silica gel to give the compound of title (1.06 g, 49.8%) as a solid.

Intermediate A-5

2-methoxy-7,7-dimethyl-6,7-dihydro-pyrrolo [3,4-b] pyridin-5-one

To a stirred solution of methyl-2-methylnicotinate (95 g, 629 mmol) in DCM (1.5 L) was added m-CPBA (119 g, 692 mmol) at 0 ° C. After the reaction mixture was stirred at room temperature for 16 hours, it was washed with a mixture of sat. ac. Na2SO3 and NaHCO3. The organic layer was then dried over anh Na2SO4, filtered and concentrated in vacuo to give a crude product (60 g, 57%), which was used in the next step reaction without further purification.

[B12- (chloromethyl) methylcotnate

The crude 3- (methoxycarbonyl) -2-methylpyridine 1-oxide (35 g, 210 mmol) was added in a small portion to POCl3 (300 g) at room temperature. After the addition, the reaction mixture was refluxed for 3 hours before being concentrated in vacuo. The residue was poured into ice water, neutralized with aq. Solution. NaHCO3 solution and extracted with EtOAc (125 ml x 3). The combined organic layers were washed with brine, dried over anh Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by flash chromatography on silica gel to give the title compound (12 g, 30 %).

IC11-2- (chloromethyl) -3- (methoxycarbon) oxide

To a stirred solution of methyl-2- (chloromethyl) nicotinate (20 g, 108 mmol) in DCM (300 ml) was added m-CPBA (20.5 g, 119 mmol) at 0 ° C. After being stirred at room temperature for 16 hours, the reaction mixture was washed with a mixture of sat. ac. Na2SO3 and NaHCO3. The organic layer was dried over anh Na2SO4, filtered and concentrated in vacuo to give the crude title product (20 g, 92%), which was used in the next step reaction without further purification.

TD16-Chloro-2- (Chloromethyl) Methyl Nicotanate

The crude 2- (doromethyl) -3- (methoxycarbonyl) pyridine 1-oxide (20 g, 99.5 mmol) was added in a small portion to POCb (200 g) at room temperature. The mixture was refluxed for 3 hours before being concentrated in vacuo. The residue was poured into ice water, neutralized with sat. ac. NaHCO3 solution, and extracted with EtOAc (125 ml x 3). The combined organic layers were concentrated to give the crude title product (17 g, 78%), which was used in the next step reaction without further purification.

[2-Chloro-6- (4-methoxybenzyl) -6,7-dihydro-5H-pyrrolo [3,4-b1pyridin-5-one

To a stirred solution of crude material of methyl 6-chloro-2- (chloromethyl) nicotinate (10 g, 45.4 mmol) in THF (150 ml) was added PMBNH2 (15.5 g, 113.5 mmol) at 0 ° C. The resulting reaction mixture was stirred at room temperature for 16 hours before being concentrated under reduced pressure to give a crude product. After washing with MTBE (100 ml x 3), the title compound (8.8 g, 67%) was obtained as a white solid. MS: 288.8 (M + H +, 1 Cl).

[F12-chloro-6- (4-methox¡-benz¡l) -7.7-d¡met¡l-6.7-d¡h¡dro-p¡rrolo [3.4-b1p¡r¡d¡n-5- ona

To a solution of 2-chloro-6- (4-methoxy-benzyl) -6,7-d¡hydro-p¡rrolo [3,4-b] pyrid¡n-5-one (5.8 g, 20.0 mmol) in THF (50 ml) was added sodium hydride (60% in petroleum jelly, 1.7 g, 42.0 mmol) at room temperature. The resulting reaction mixture was stirred for 30 min before iodomethane (6.0 g, 42.0 mmol) was added. After stirring at room temperature overnight, the mixture was quenched with water and extracted with EtOAc. The organic layer was then washed with brine, dried over anh. Na2SO4, filtered and concentrated in vacuo to give the crude product which was then purified by flash chromatography on silica gel (5% to 20% of ethyl acetate in DCM). The title compound (3.8 g, 57%) was obtained as a white solid. Em: 316.2 (M + H +).

[G12-methox¡-6- (4-methox¡-benz¡l) -7.7-d¡met¡l-6.7-d¡h¡dro-p¡rrolo [3.4-b1p¡r¡d¡n-5 -ona

To a solution of 2-doro-6- (4-methoxy-benzyl) -7,7-dimethyl-6,7-dihydro-pyrrolo [3,4-b] pyridin-5-one (3.15 g, 10 mmol) in DMF (30 ml) was added sodium methanolate (0.813 g, 15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours before it was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound (2.8 g, 90%) as a solid. MS: 313.1 (M + H +).

[H] 2-methox¡-7.7-d¡metal-6.7-dihydro-p¡rrolo [3.4-b1p¡r¡d¡n-5-one

To a solution of 2-methoxy-6- (4-methoxy-benzyl) -7,7-di-methyl-6,7-dihydro-pyrrolo [3,4-b] p¡r¡d¡n-5-one (0.31 g, 1.0 mmol) in CH3CN (5 ml) was added ceric ammonium nitrate (1.64 g, 3.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours before water and EtOAc were added to the mixture. The organic layer was separated, dried over anh Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by flash chromatography on silica gel to give the title compound (0.12 g, 63 %) as a solid. MS: 193.1 (M + H +).

Intermediate A-6

5'-chlorospiro [cyclopropane-1,3'-isoindolin] -1'-one

[A11- (2-bromo-5-chloro-phenyl) cyclopropanamine

To a stirred solution of 2-bromo-5-chlorobenzonetrio (10 g, 46 mmol) and Ti (O¡-Pr) 4 (16.64 ml, 55 mmol) in THF (200 ml) a - 78 ° C EtMgBr (138 ml, 138 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stir for 2 hours. BF3-Et2O (17.2 mL) was added, and the solution was stirred for another 16 hours before it was quenched with aq. HCl and washed with EtOAc. The aqueous phase was adjusted to pH ~ 10 with ac solution. NaOH, and extracted with EtOAc three times. The combined organic layers were concentrated to give a crude product which was purified by flash chromatography on silica gel to give the title compound (2 g, 17.6%). MS: 246.7 (M + H +, 1Cl) as an oil.

[B15'-chlorosp¡ro [cyclopropane-1.3'-iso¡ndol¡n1-1'-one

A mixture of 1- (2-bromo-5-chlorophenyl) cyclopropanamine (2 g, 8.1 mmol), Pd (dppf) Cl2 (0.2 g), DIPEA (3.1 g, 24.3 mmol) was stirred ) in DMF (20 ml) in an autoclave under 2 MPa CO (g) at 130 ° C for 16 hours. The reaction mixture was diluted with EtOAc (300 ml), and washed with brine. The organic layer was dried over anh Na2SO4, filtered and concentrated under reduced pressure to give a crude product which was purified by flash chromatography on silica gel to give the title compound (700mg, 44.6%) as a solid yellow. MS: 193.8 (M + H +, 1 Cl).

Intermediate B-1

6-chloro-2- [5- (2,6-diazaspiro [3.3] heptan-2-yl) -3-pyridyl] -3,4-dihydroisoquinolin-1-one

A mixture of 6-chloro-3,4-dihydro-2H-isoquinolin-1-one (intermediate A-1, 380 mg, 2 mmol), 3,5-diiodopyridine (1,192 g, 3.6 mmol), Cul (152 mg, 0.8 mmol), (1S, 2S) -cyclohexane-1,2-diamine (182.4 mg, 1.6 mmol) and K3PO4 (848 mg, 4 mmol) in dioxane (5 ml) up to reflux temperature for 3 hours. After cooling to room temperature, the mixture was poured into sat. ac. NaHCO3 (20 ml) and extracted with EtOAc (3 x 30 ml). The combined organic layers were washed with brine, dried over anh Na2SO4, filtered and concentrated in vacuo to give a crude product, which was then purified by flash chromatography on silica gel to give the title compound (350 mg , 46%) as a white solid. MS: 385.1 (M + H +).

[B16- [5- (6-chloro-1-oxo-3.4-d¡h¡dro¡soqu¡nol¡n-2-¡l) -3-p¡r¡d¡l1-2.6-d¡azaesp Ro

tere-butyl r3.31-heptane-2-carboxylate

To a solution of 6-doro-2- (5-iodo-3-pyridyl) -3,4-dihydroisoquinolin-1-one (480 mg, 1.25 mmol), 2,6-diazaspiro [3.3] heptane-2 tert-butyl carboxylate-oxalate (500 mg, 1.74 mmol), Pd2dba3 (100 mg, 0.11 mmol), BINAP (120 mg, 0.19 mmol) and tBuONa (400 mg, 4.8 mmol) 10 drops of triethylamine were added in toluene (10 ml). The resulting reaction mixture was then heated to 85 ° C for 2 hours. After room temperature had cooled, the mixture was poured into brine and extracted with DCM (3 x 10 ml). The combined organic layers were washed with brine, dried over anh Na2SO4, filtered and concentrated in vacuo to give a crude product, which was then purified by flash chromatography on silica gel to give the title compound (283 mg , 50%) as a brown solid. MS: 455.1 (M + H +).

[C] 6-chloro-2- [5- (2.6-d¡azasp¡ro [3.31heptan-2-¡l) -3-p¡r¡d¡l1-3.4-d¡h¡droisoqu¡nol¡ n-1-one

6- [5- (6-chloro-1-oxo-3,4-d¡h¡dro¡soqu¡nol¡n-2-¡l) -3-pyrid¡l] -2.6 Fercbutyl dihazaspiro [3.3] heptane-2-carboxylate (454 mg, 1.0 mmol) with TFA (5 ml) in DCM (5 ml) at 0 ° C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1.5 hours before being concentrated under reduced pressure to give the desired title compound (350 mg, 98%) as an oil. MS: 355.1 (M + H +). It was used directly in the next step without further purification.

Intermediate B-2

5-chloro-2- [5- (2,6-diazaspiro [3.3] heptan-2-yl) -3-pyridyl] -3-methyl-isoindolin-1-one

In a 75 ml sealed tube, 3-bromo-5-iodo-pyridine (4.3 g, 15 mmol), 2- (5-bromo-3-pyridyl) -5-chloro-3-methyl-isoindolin were dissolved -1-one (intermediate A-2, 1.81 g, 10 mmol), Cul (1.4 g, 6 mmol), K3PO4 (4.24 g, 20 mmol) and (+) - (S, S) -1,2-diaminocyclohexane (0.7 ml, 6 mmol) in dioxane (20 ml). The resulting reaction mixture was heated at 120 ° C for 3 hours before it was poured into water (50 ml) and extracted with EtOAc (2 x 125 ml). The combined organic layers were washed with brine, dried over anh. Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by flash chromatography on silica gel (gradient 0-60% EtOAc-hexane ) to give the title compound (2.8 g, 83.1%) as a light yellow solid. MS: 337.1 and 339.1 (M + H +).

[B16- [5- (5-chloro-3-methyl-1-oxo-¡so¡ndol¡n-2-¡l) -3-p¡r¡d¡l1-2.6-d¡azaesp¡ tert-butyl ro [3.31lheptane-2-carboxylate

A mixture of 2- (5-bromo-3-pyridyl) -5-doro-3-methyl-isoindolin-1-one (674 mg, 2 mmol), 2,6-diazaspiro [3.3] heptane-2- tert-butyl carboxylate-oxalate (870 mg, 3 mmol), Pd2 (dba) 3 (137 mg), BINAP (165 mg), t-BuONa (580 mg, 6 mmol) and TEA (1 ml, 7.2 mmol) in toluene (20 ml) at 110 ° C for 12 hours. After cooling to room temperature, the reaction mixture was poured into water (20 ml) and extracted with EtOAc (2 x 100 ml). The combined organic layers were washed with brine, dried over anh Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by flash chromatography on silica gel (30-100% EtOAc-hexane gradient ) to give the title compound (800mg, 88.9%) as a light yellow foam. MS: 455.2 (M + H +).

[C] 5-chloro-2- [5- (2.6-d¡azasp¡ro [3.31heptan-2-¡l) -3-p¡r¡dil1-3-methyl-¡so¡ndol¡n -1-one

A solution of 6- [5- (5-chloro-3-methyl-1-oxo-¡so¡ndol¡n-2-¡l) -3-pyrid¡l] -2.6 -d¡azasp¡ro [3.3] tert-butyl heptane-2-carboxylate (800 mg, 0.889 mmol) and TFA (2 ml) in DCM (5 ml) at room temperature for 2 hours before being concentrated in vacuo to give the crude title compound (900mg) as a pale yellow oil. MS: 355.1 (M + H +). It was used directly in the next step without further purification.

Intermediate B-3

5-chloro-2- [5- (2,6-diazaspiro [3.3] heptan-2-yl) -3-pyridyl] -3,3-dimethyl-isoindolin-1-one

A mixture of 5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one (intermediate A-3, 2.5 g, 12.8 mmol), 3 , 5-diiodopyridine (8.7 g, 26.8 mmol), CuI (2.0 g, 10.2 mmol), (1S, 2S) -cidohexane-1,2-diamine (2.0 g, 20, 9 mmol) and K3PO4 (6.3 g, 28.5 mmol) in dioxane (40 at reflux temperature for 3 hours. After cooling to room temperature, the mixture was poured into sat.aq NaHCO3 solution (20 ml ) and extracted with EtOAc (3 x 30 mL) The combined organic layers were washed with brine, dried over anh Na2SO4, filtered and concentrated in vacuo to give a crude product, which was then purified by flash chromatography on silica gel to give the title compound (2.5 g, 49%) as a white solid MS: 399.0 (M + H +).

rB! 6-r5- (6-chloro-1.1-d¡met¡l-3-oxo-¡so¡ndol¡n-2-¡l) -3-p¡r¡d¡l1-2.6-d¡azaesp¡ ror3.31heptane-2-carboxytere-butyllate

To a solution of 5-chloro-2- (5-iodo-3-p¡r¡d¡l) -3,3-d¡met¡l-¡so¡ndol¡n-1-one (300 mg, 1.25 mmol), 2,6-diazaspiro [3.3] heptane-2-carboxylate-tere-butyl oxalate (500 mg, 1.74 mmol), Pd2dba3 (100 mg, 0.11 mmol), BINAP ( 120 mg, 0.19 mmol) and tBuONa (400 mg, 4.8 mmol) in toluene (10 ml) were added 10 drops of triethylamine. The reaction mixture was heated to 85 ° C for 2 hours. After cooling to room temperature, the mixture was poured into brine and extracted with DCM (3x10 ml). The combined organic layers were washed with brine, dried over anh Na2SO4, filtered, and concentrated in vacuo to give a crude product, which was then purified by flash chromatography on silica gel to give the title compound (460 mg , 52%) as a brown solid. MS: 469.1 (M + H +).

[C15-doro-2-r5- (2.6-d¡azaesp¡ror3.31heptan-2-¡l) -3-p¡r¡d¡l1-3.3-d¡met¡l-¡so¡ndol¡n -1-one

6- [5- (6-Chloro-1,1-d¡metal-3-oxo-¡so¡ndol¡n-2-¡l) -3-pmd¡l] -2.6- tere-butyl diazaspiro [3.3] heptane-2-carboxylate (920 mg, 1.96 mmol) with TFA (10 ml) in DCM (12 ml) at 0 ° C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure to give the title compound as an oil, which was used directly in the next step without further purification. MS: 369.1 (M + H +).

Intermediate B-4

2- [5- (2,6-diazaspiro [3.3] heptan-2-yl) -3-pyridyl] -3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile

ÍA! 2- (5-vodo-3-plrldll) -3.3-dlmethyl-1-oxo-lsolndolln-5-carbonltrllo

A solution of 3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile (intermediate A-4, 650 mg, 3.5 mmol), 3,5-diiodopyridine (2.0 g, 6.0 mmol) was heated ), CuI (200 mg, 1.05 mmol), (1S, 2S) -cidohexane-1,2-diamine (240 mg, 2.1 mmol) and K3PO4 (1.5 g, 7 mmol) in dioxane (8 ml) at reflux temperature for 4 hours. After cooling to room temperature, the mixture was poured into sat. ac. NaHCO3 (20 ml) and extracted with EtOAc (3 x 30 ml). The combined organic layers were washed with brine, dried over anh Na2SO4, filtered and concentrated in vacuo to give a crude product, which was then purified by flash chromatography on silica gel to give the title compound (350 mg , 26%) as a white solid. MS: 389.6 (M + H +).

[B16- [5- (6-c¡ano-1.1-d¡met¡l-3-oxo-¡so¡ndol¡n-2-¡l) -3-p¡r¡d¡l1-2.6- d¡azasp¡ro [3.31 tere-butyl heptane-2-carboxylate

To a solution of 2- (5-iodo-3-pyridyl) -3,3-dimethyl-1 -oxo-isoindolin-5-carbonitrile (561 mg, 1.44 mmol), 2,6-diazaspiro [3.3] heptane Tere-butyl -2-carboxylate-oxalate (500 mg, 1.74 mmol), Pd2dba3 (100 mg, 0.11 mmol), BINAP (120 mg, 0.19 mmol) and tBuONa (400 mg, 4.8 mmol) in toluene (10 ml) were added 10 drops of triethylamine. The reaction mixture was heated to 100 ° C for 3 hours. After cooling to room temperature, the mixture was poured into brine and extracted with EtOAc (3x10 ml). The combined organic layers were washed with brine, dried over anh Na2SO4, filtered and concentrated in vacuo to give a crude product, which was then purified by flash chromatography on silica gel to give the title compound (300 mg 45%) as a brown solid. MS: 460.1 (M + H +).

[C12- [5- (2.6-d¡azaesp¡ro [3.31heptan-2-¡l) -3-p¡r¡d¡l1-3.3-d¡met¡l-1-oxo-¡so¡ndol N-5-carbon

6- [5- (6-cyano-1,1-d¡met¡l-3-oxo-¡so¡ndol¡n-2-¡l) -3-pyrid¡l] - was treated 2,6-d¡azaesp¡ro [3.3] heptane-2-carbox¡lato of terebutilo (300 mg, 0.65 mmol) with TFA 30% in DCM (12 ml) at room temperature for 15 min. The reaction solution was concentrated under reduced pressure to give the title compound as an oil, which was used directly in the next step without further purification. MS: 360.1 (M + H +)

Intermediate B-5

6- [5- (2,6-diazaspiro [3.3] heptan-2-yl) -3-pyridyl] -2-methoxy-7,7-dimethyl-pyrrole [3,4-b] pyridin-5-one

In a 75 ml sealed tube. 3,5-diiodopyridine (2.5 g, 7.5 mmol) was dissolved. 2-methoxy-7,7-dimethyl-6H-pyrrolo [3,4-b] p¡r¡d¡n-5-one (intermediate A-5. 576 mg. 3 mmol). CuI (345 mg, 1.8 mmol). K3pO4 (1.28 g. 6 mmol) and (+) - (S.S) -1.2-diaminocyclohexane (0.12 ml, 1 mmol) in dixane (20 ml). The resulting reaction mixture was heated at 120 ° C for 3 hours before it was poured into water (50 ml) and extracted with EtOAc (2 x 125 ml). The combined organic layers were washed with brine. dried over anh Na2SO4. filtered and concentrated in vacuo to give a crude product. which was purified by silica gel flash chromatography (gradient 0-60% EtOAc-hexane) to give the title compound (474 mg, 40.1%) as a solid light yellow. MS: 396.1 (M + H +).

[B1 6- [5- (2-methox¡-7.7-d¡met¡l-5-oxo-p¡rrolo [3.4-b1p¡r¡d¡n-6-¡l) -3-p¡r ¡D¡l1-2.6-d¡azasp¡ro [3.31heptane-2-carboxylate of tert-butyl

A mixture of 6- (5-vodo-3-p¡r¡d¡l) -2-methox¡-7.7-d¡met¡lp¡rrolo [3.4-b1p¡r¡d¡n- 5-one (395 mg, 1 mmol). 2.6-d¡azasprio [3.31heptane-2-carboxylate-tert-butyl oxalate (435 mg, 1.5 mmol). Pd2 (dba) 3 (70 mg). BINAP (85 mg). t-BuONa (290 mg, 3 mmol) and TEA (1 ml, 7.2 mmol) in toluene (20 ml) at 110 ° C for 12 hours. After cooling to room temperature. The reaction mixture was poured into water (20 ml) and extracted with EtOAc (2 x 100 ml). The combined organic layers were washed with brine. dried over anh Na2SO4. filtered and concentrated in vacuo to give a crude product. which was purified by silica gel flash chromatography (30-100% EtOAc-hexane gradient) to give the title compound (350 mg, 75.2%) as a yellow foam. I am sure. MS: 466.1 (M + H +).

[C16- [5- (2.6-d¡azaesp¡ro [3.31heptan-2-¡l) -3-p¡r¡d¡l1-2-methox¡-7.7-d¡met¡lp¡rrolo [3.4 -b1p¡r¡d¡n-5-one

A solution of 6- [5- (2-methoxy-7.7-d¡met¡l-5-oxo-p¡rrolo [3.4-b1p¡r¡d¡n-6-¡l ) -3-p¡r¡d¡l1-2.6-d¡azaesp¡ro [3.31heptane-2-carboxylic acid ferc-butyllate (350 mg, 0.75 mmol) and TFA (2 ml) in d Cm (5 ml) at temperature environment for 2 hours. The resulting mixture was concentrated in vacuo to give the crude title compound (450 mg) as a pale yellow oil, which was used directly in the next step without further purification. MS: 366.1 (M + H +).

Intermediate B-6

5'-chloro-2 '- [5- (2,6-diazaspiro [3.3] heptan-2-yl) -3-pyridyl] spiro [cyclopropane-1,3'-isoindolin] -1'-one

[Al 5'-chloro-2 '- (5-vodo-3-p¡r¡d¡l) esp¡ro [cyclopropane-1.3'-iso¡ndol¡n1-1'-one

In a 75 ml sealed tube, 3,5-diiodopyridine (2.5 g, 7.5 mmol), 5'-chlorospiro [cyclopropane-1,3'-isoindolin] -1'-one (intermediate A-6, 579 mg, 3 mmol), Cul (345 mg, 1.8 mmol), K3PO4 (1.28 g, 6 mmol) and (+) - (S, S) -1,2-diaminocyclohexane (0.12 ml, 1 mmol) in dioxane (20 ml). The resulting reaction mixture was heated at 120 ° C for 3 hours before it was poured into water (50 ml) and extracted with EtOAc (2 x 125 ml). The combined organic layers were washed with brine, dried over anh. Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by flash chromatography on silica gel (gradient 0-60% EtOAc-hexane ) to give the title compound (436 mg, 36.7%) as a light yellow solid. MS: 397.1 (M + H +).

[B16- [5- (6'-chloro-3'-oxo-spiro [cyclopropane-1, 1 '-¡so¡ndol¡n1-2'-¡l) -3-p¡r¡d¡ 11-2,6-d¡azasp¡ro [3.31heptane-2-carboxytere-butyllate

A solution of 5'-chloro-2 '- (5-iodo-3-p¡r¡d¡l) esp¡ro [cyclopropane-1,3'-¡so¡ndol¡n] -1 was stirred '-one (396 mg, 1 mmol), 2,6-diazaspiro [3.31heptane-2-carboxylate-tere-butyl oxalate (435 mg, 1.5 mmol), Pd2 (dba) 3 (70 mg), BINAP (85 mg), t-BuONa (290 mg, 3 mmol) and TEA (1 ml, 7.2 mmol) in toluene (20 ml) at 110 ° C for 12 hours. After cooling to room temperature, the reaction mixture was poured into water (20 ml) and extracted with EtOAc (2 x 100 ml). The combined organic layers were washed with brine, dried over anh Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by flash chromatography on silica gel (30-100% EtOAc-hexane gradient ) to give the title compound (414 mg, 88.9%) as a light yellow foam. MS: 467.1 (M + H +).

[C15'-chloro-2 '- [5- (2.6-d¡azasp¡ro [3.31heptan-2-¡l) -3-p¡r¡d¡l1esp¡ro [cyclopropane-1.3'-¡ so¡ndol¡n1-1'-one

A solution of 6- [5- (6'-chloro-3'-oxo-spiro [cyclopropane-1,1'-isoindolin] -2'-yl) -3-pyridyl] -2,6-diazaspiro [ 3.3] tert-butyl heptane-2-carboxylate (414 mg, 0.889 mmol) and TFA (2 ml) in DCM (5 ml) at room temperature for 2 hours. The resulting mixture was concentrated in vacuo to give the crude title compound (550 mg) as a pale yellow oil, which was used directly in the next step without further purification. MS: 367.1 (M + H +).

Intermediate B-7

5-chloro-2- [5- (2,6-diazaspiro [3.3] heptan-2-yl) -4-methyl-3-pyridyl] -3-methyl-isoindolin-1-one

A solution of 3,5-dibromo-4-methyl-pyridine (10.0 g, 39.8 mmol), KI (70.0 g, 422 mmol), W, W-dimethylethane-1,2-diamine was heated (4.0 g, 45.4 mmol), Cul (4.0 g, 21.0 mmol) in dioxane (150 ml) at 130 ° C for 16 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (8.9 g, 65%) as a yellow solid. MS: 346.1 (M + H +).

[B15-doro-2- (5-iodo-4-methyl-3-p¡r¡d¡l) -3-methyl-¡so¡ndol¡n-1-one

A mixture of 3,5-diiodo-4-methyl-pyridine (3.45 g, 10.0 mmol), 5-chloro-3-methyl-isoindolin-1-one (intermediate A-2, 1.0 g, 5.5 mmol), frans-cyclohexane-1,2-diamine (500mg, 4.3 mmol) and K3PO4 (2.7 g, 12.2 mmol) in dioxane (30 ml) at 120 ° C for 6 hours. After cooling to room temperature, the solvent was evaporated. The residue was purified by silica gel flash chromatography (PE: EtOAc = 3: 1) to give the title compound (600 mg, 15%) as a yellow solid. MS: 399.3 (M + H +).

[C] 6- [5- (5-doro-3-methyl-1-oxo-¡so¡ndol¡n-2-¡l) -4-methyl-3-p¡r¡d¡ 11-2.6-d¡azasp¡ro [3.31heptane-2-tert-butyl carboxylate

A mixture of 5-chloro-2- (5-iodo-4-methyl-3-pyridyl) -3-methyl-isoindolin-1-one (300 mg, 0.75 mmol), 2,6-diazaspiro [ 3.3] tert-butyl heptane-2-carboxylate-oxalate (300 mg, 1.04 mmol), Pd2 (dba) 3 (80 mg), BINAP (80 mg), tBuONa (240 mg, 2.5 mmol) and triethylamine (0.5 ml) in toluene (5 ml) at 100 ° C for 10 hours. After cooling to room temperature, the reaction mixture was diluted with sat. ac. NaCl (5 ml), extracted with EtOAc (4 x 10 ml), dried over anh. Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by flash chromatography on silica gel (PE : EtOAc = 2: 1) to give the title compound (160mg, 45%) as a yellow solid. MS: 369.1 (M + H +).

[D] 5-chloro-2- [5- (2.6-d¡azasp¡ro [3.31heptan-2-¡l) -4-methyl-3-p¡r¡d¡l1-3-methyl- So¡ndol¡n-1-one

A solution of 6- [5- (5-chloro-3-methyl-1-oxo-¡so¡ndol¡n-2-¡l) -4-methyl-3-p¡r¡d¡ was stirred. tert-Butyl l] -2,6-diazaspiro [3.3] heptane-2-carboxylate (160 mg, 0.34 mmol) in DCM / TFA (4 ml / 4 ml) at room temperature for 2 hours . The solvent was then evaporated to dryness and provided the title compound (300mg, 100%) as a brownish oil. MS: 469.1 (M + H +).

Intermediate B-8

5-chloro-2- [5- (2,7-diazaspiro [3.5] nonan-2-yl) -3-pyridyl] -3,3-dimethyl-isoindolin-1-one

[A12- (5-bromo-3-pyridyl) -5-chloro-3,3-dimethyl-isoindolin-1-one

In a 75 ml sealed tube, 3-bromo-5-iodo-pyridine (4.3 g, 15 mmol), 5-chloro-3,3-dimethyl-isoindolin-1-one (intermediate A-3, 1.95 g, 10 mmol), Cul (1.4 g, 6 mmol), K3PO4 (4.24 g, 20 mmol) and (+) - (S, S) -1,2-diaminocyclohexane (0.7 ml, 6 mmol) in dioxane (20 ml). The resulting reaction mixture was heated at 120 ° C for 3 hours before it was poured into water (50 ml) and extracted with EtOAc (2 x 125 ml). Organic layers were washed combined with brine, dried over anh Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by flash chromatography on silica gel (0-60% EtOAc-hexane gradient) to provide the compound of the title (2.5 g, 71.2%) as a light yellow solid. MS: 351.1 and 353.1 (M + H +).

[B12- [5- (6-chloro-1.1-d¡met¡l-3-oxo-¡so¡ndol¡n-2-¡l) -3-p¡r¡d¡l1-2.7-d¡ azaspiro [3.51 tere-butyl nonane-7-carboxylate

A solution of 2- (5-bromo-3-p¡r¡d¡l) -5-chloro-3,3-d¡met¡l-¡so¡ndol¡n-1-one (351 mg , 1 mmol), 2.7 diazaspiro [3.5] tere-butyl nonane-7-carboxylate (400 mg, 1.7 mmol), Pd2 (dba) 3 (70 mg), BINAP (85 mg), t -BuONa (400 mg, 4 mmol) and TEA (0.5 ml, 4 mmol) in toluene (10 ml) at 110 ° C for 12 hours. After cooling to room temperature, the reaction mixture was poured into water (20 ml) and extracted with EtOAc (2 x 100 ml). The combined organic layers were washed with brine, dried over anh Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by flash chromatography on silica gel (30-100% EtOAc-hexane gradient ) to provide the title compound (370 mg, 74.6%) as a pale yellow oil. MS: 497.1 (M + H +).

[C15-chloro-2- [5- (2.7-d¡azasp¡ro [3.51nonan-2-¡l) -3-p¡r¡d¡l1-3.3-d¡met¡l-¡so¡ndol N-1-one

A solution of 2- [5- (6-chloro-1,1-d¡metal-3-oxo-¡so¡ndol¡n-2-yl) -3-p¡r¡d¡l was stirred ] Tere-butyl] -2,7-diazaspiro [3.5] nonane-7-carboxylate (370 mg, 0.746 mmol) and TFA (1 ml) in DCM (3 ml) at room temperature for 2 hours. The resulting mixing solution was concentrated in vacuo to give a crude product (400 mg) as a light yellow oil, which was used directly in the next step without further purification. MS: 397.1 (M + H +).

Intermediate B-9

5-chloro-2- [5- (2,7-diazaspiro [3.5] nonan-7-yl) -3-pyridyl] -3,3-dimethyl-isoindolin-1-one

A solution of 2- (5-bromo-3-pyridyl) -5-chloro-3,3-dimethyl-isoindolin-1-one (351 mg, 1 mmol, intermediate B-8 [A1), 2.7 -diazaspiro [3.51 tere-butyl nonane-2-carboxylate (400 mg, 1.7 mmol), Pd2 (dba) 3 (70 mg), BINAP (85 mg), t-BuONa (400 mg, 4 mmol) and TEA (0.5 ml, 4 mmol) in toluene (10 ml) at 11 ° C for 12 hours. After the Cooling to room temperature, the reaction mixture was poured into water (20 ml) and extracted with EtOAc (2 x 100 ml). The combined organic layers were washed with brine, dried over anh Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by flash chromatography on silica gel (30-100% EtOAc-hexane gradient ) to provide the title compound (330 mg, 66.6%) as a pale yellow oil. MS: 497.1 (M + H +).

[B! 5-chloro-2- [5- (2,7-diazaspiro [3.5lnonan-7-yl) -3-pyridyl-3,3-dimethyl-isoindolin-1-one

A solution of 7- [5- (6-chloro-1,1-dimethyl-3-oxo-isoindolin-2-yl) -3-pyridyl] -2,7-diazaspiro [3.5] nonane-2-carboxylate was stirred of tere-butyl (330 mg, 0.666 mmol) and TFA (1 ml) in DCM (3 ml) at room temperature for 2 hours. The resulting mixture was concentrated in vacuo to give a crude product (400 mg) as a pale yellow oil, which was used in the next step without further purification. MS: 397.1 (M + H +).

Example 1

5-chloro-3,3-dimethyl-2- [5- [2- (1-methylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] -heptan-6-yl] -3-pyridyl] isoindolin- 1 -one

To a solution of 5-chloro-2- [5- (2,6-diazaspiro [3.3] heptan-2-yl) -3-pyridyl] -3,3-dimethyl-isoindolin-1-one (intermediate B-3 , 1.6 g, 3.2 mmol) and 1-methylpyrazole-4-carboxylic acid (1.1g, 8.7 mmol) in DCM was added BOP-Cl (3.7 g, 8.4 mmol) and DIEPA (2.0 g, 15.5 mmol) at 0 ° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. Brine was added to quench the reaction and the mixture was extracted with DCM twice. The organic layers were combined, washed with brine, dried over anh Na2SO4, filtered and concentrated in vacuo to give a yellow oily residue, which was purified by flash chromatography on silica gel to give the title compound (680 mg, 45%) as a white foam. MS: 477.3 (M + H +).

The following examples listed in Table 1 were prepared analogously to the procedure described for the preparation of Example 1. And if necessary, chiral separation was used to give the respective chiral compounds.

Table 1

Example A

A compound of formula (I) can be used in a manner known per se as an active ingredient for the production of tablets of the following composition:

Per tablet

Active ingredient 200 mg

Microcrystalline cellulose 155 mg

Corn starch 25 mg

Talc 25 mg

Hydroxypropylmethylcellulose 20 mg

425 mg

Example B

A compound of formula (I) can be used in a manner known per se as an active ingredient for the production of capsules of the following composition:

Per capsule

Active ingredient 100.0 mg

Corn starch 20.0 mg

Lactose 95.0 mg

Talc 4.5 mg

Magnesium stearate 0.5 mg

220.0 mg

Claims (14)

1. Compounds of formula (I)

in which R1, R2, R3, and R4 are independently selected from H, alkyl, and cycloalkyl; or R1 and R2 together form -CH2-CH2-; R5 and R6 are independently selected from H or alkyl; A1 is -CH- or -N-; A2 is -C (O) -; R12 is heteroaryl or substituted heteroaryl, wherein substituted heteroaryl is substituted with one to three substituents independently selected from alkyl, cycloalkyl, haloalkyl, hydroxy, alkoxy, cyano, and halogen; R13 is halogen, cyano, alkoxy, or haloalkoxy; R15 is H, alkyl, cycloalkyl, or halogen; m is zero or 1; and R9 and R14 together form -CH2-, R10 and R11 together form -CH2-, n is 1 and p is zero; or R9 and R14 together form -CH2-CH2-, R10 and R11 together form -CH2-, n is 1 and p is 1 and R7 and R8 are independently selected from H or alkyl; or R7 and R14 together form -CH2-, R8 and R11 together form -CH2-CH2-, n is 1, p is 1 and R9 and R10 are independently selected from H or alkyl; and pharmaceutically acceptable salts thereof. 2. A compound according to claim 1, wherein R1 and R2 are alkyl or R1 and R2 together form -CH2-CH2-. 3. A compound according to any one of claims 1 and 2, wherein R1 and R2 are alkyl. 4. A compound according to any one of claims 1 to 3, wherein A1 is -CH-. 5. A compound according to any one of claims 1 to 4, wherein R9 and R14 together form -CH2-, R10 and R11 together form -CH2-, n is 1 and p is zero. 6. A compound according to any one of claims 1 to 5, wherein the heteroaryl group of R12 is selected from imidazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl and pyrimidinyl. 7. A compound according to any one of claims 1 to 6, wherein R12 is alkyl-substituted pyrazolyl or alkyl-substituted pyridinyl. 8. A compound according to any one of claims 1 to 7, wherein R12 is alkyl substituted pyrazolyl. 9. A compound according to any one of claims 1 to 8, selected from 5-doro-3,3-dimethyl-2- [5- [2- (1-methylpyrazole-4-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] isoi ndolin-1-one; 5-chloro-2- [5- [2- (1-ethylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -3,3-dimethyl-isoindolin- 1-one; 5-chloro-2- [5- [2- (1-isopropylpyrazole-4-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] -3,3-dimethyl- isoi ndolin-1-one; 5-chloro-3,3-dimethyl-2- [5- [2- (1-methylimidazole-2-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1 -one; 5-chloro-3,3-dimethyl-2- [5- [2- (2-methylpyrazole-3-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] isoi ndolin-1-one; 5-chloro-3,3-dimethyl-2- [5- [2- (3-methylimidazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1 -one; 5-chloro-3,3-dimethyl-2- [5- [2- (4-methylpyridine-3-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1 -one; 3.3- dimethyl-2- [5- [2- (1-methylpyrazole-4-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pi ridyl] -1 -oxo-isoindolin- 5-carbonitrile; 2- [5- [2- (1-Ethylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -3,3-dimethyl-1-oxo-isoindoline- 5-carbonitrile; 2- [5- [2- (1-isopropylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -3,3-dimethyl-1-oxo-isoindoline- 5-carbonitrile; 3.3- dimethyl-2- [5- [2- (1-methylimidazole-2-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -1-oxo-isoindolin-5- carbonitrile; 3.3- dimethyl-2- [5- [2- (2-methylpyrazole-3-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] -1 -oxo-isoindolin- 5-carbonitrile; 3.3- dimethyl-2- [5- [2- (3-methylimidazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -1-oxo-isoindolin-5- carbonitrile; 3.3- dimethyl-2- [5- [2- (4-methylpyridine-3-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -1-oxo-isoindolin-5- carbonitrile; 2-methoxy-7,7-dimethyl-6- [5- [2- (1-methylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] pyrrolo [3 , 4-b] pyridin-5-one; 2-methoxy-7,7-dimethyl-6- [5- [2- (4-methylpyridine-3-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] pyrrolo [3 , 4-b] pi ridin-5-one; 2-methoxy-7,7-dimethyl-6- [5- [2- (2-methylpyrazole-3-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] pyrrolo [3 , 4-b] pyridin-5-one; 5-chloro-3-methyl-2- [5- [2- (1-methylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1-one ; 5'-chloro-2 '- [5- [2- (1-methylpyrazole-4-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] spiro [cyclopropane-1, 3'-isoindolin] -1'-one; 5'-chloro-2 '- [5- [2- (4-methylpyridine-3-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] spiro [cyclopropane-1, 3'-isoindolin] -1'-one; 5'-chloro-2 '- [5- [2- (2-methylpyrazole-3-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] spiro [cyclopropane-1, 3'-isoindolin] -1'-one; (3R or 3S) -5-chloro-3-methyl-2- [5- [2- (1-methylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl ] isoindolin-1-one; (3S or 3R) -5-chloro-3-methyl-2- [5- [2- (1-methylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl ] isoindolin-1-one; 5-chloro-2- [5- [2- (4-methoxypyridine-3-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -3,3-dimethyl-isoindolin- 1-one; 5-chloro-2- [5- [2- (3,6-dimethylpyrazine-2-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] -3,3- dimethyl isoi ndolin-1-one; 5-chloro-2- [5- [2- (1,5-dimethylpyrazole-4-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] -3,3- dimethyl isoi ndolin-1-one; 5-chloro-3,3-dimethyl-2- [5- [2- (3-methylisoxazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1 -one; 5-doro-3,3-dimethyl-2- [5- [2- (6-methylpirazine-2-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] isoi ndolin-1-one; 5-doro-3,3-dimethyl-2- [5- [2- (4-methylpyrimidine-5-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1 -one; 5-doro-3,3-dimethyl-2- [5- [2- (5-methylpirazine-2-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] isoi ndolin-1-one; 5-doro-2- [5- [2- (2,5-dimethylpyrazole-3-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] -3,3- dimethyl-isoindolin-1-one; 5-doro-3,3-dimethyl-2- [5- [2- (5-methyloxazole-4-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] isoi ndolin-1-one; 5-doro-3,3-dimethyl-2- [5- [2- (pi rimidine-2-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1- ona; 5-doro-3,3-dimethyl-2- [5- [2- (5-methylpyrimidine-2-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1 -one; 5-doro-2- [5- [2- [3- (difluoromethyl) -1-methyl-pyrazole-4-carbonyl] -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] - 3,3-dimethylisoindolin-1-one; 5- [6- [5- (6-doro-1,1-dimethyl-3-oxo-isoindolin-2-yl) -3-pyridyl] -2,6-diazaspiro [3.3] heptane-2-carbonyl] pyridine -3-carbonitrile; 5-doro-2- [5- [2- (3-methoxypyrazine-2-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -3,3-dimethyl-isoindolin- 1-one; 5-doro-3,3-dimethyl-2- [5- [2- (pyrazine-2-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1- ona; 5-doro-3,3-dimethyl-2- [5- [2- (5-methylisoxazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1 -one; 5-doro-3,3-dimethyl-2- [5- [2- (pi rimidine-5-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1- ona; 5-doro-3,3-dimethyl-2- [5- [2- (4-methyloxazole-5-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] isoi ndolin-1-one; 5-doro-3,3-dimethyl-2- [5- [2- (oxazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1-one ; 5-doro-3,3-dimethyl-2- [5- [2- (2-methyloxazole-5-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] isoi ndolin-1-one; 5-doro-2- [5- [2- (2,4-dimethyloxazole-5-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] -3,3- dimethyl-isoindolin-1-one; 5-doro-3,3-dimethyl-2- [5- [2- (2-methyloxazole-4-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] isoi ndolin-1-one; 2- [6- [5- (6-doro-1,1-dimethyl-3-oxo-isoindolin-2-yl) -3-pyridyl] -2,6-diazaspiro [3.3] heptane-2-carbonyl] pyridine -3-carbonitrile; 5-doro-2- [5- [2- (5-doro-2-methyl-pyrimidine-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -3, 3-dimethyl-isoindolin-1-one; 5-doro-2- [5- [2- (4,6-dimethylpyrimidine-5-carbonyl) -2,6-diazaspi ro [3.3] heptan-6-yl] -3-pyridyl] -3,3-dimethyl -isoindolin-1-one; 5- doro-2- [5- [2- (2,4-dimethylpyridine-3-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -3,3-dimethyl- isoindolin-1-one; 3- [6- [5- (6-doro-1,1-dimethyl-3-oxo-isoindolin-2-yl) -3-pyridyl] -2,6-diazaspiro [3.3] heptane-2-carbonyl] pyridine -4-carbonitrile; (3S or 3R) -5-doro-2- [5- [2- (1-ethylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -3- methyl-isoindolin-1-one; (3R or 3S) -5-doro-2- [5- [2- (1-ethylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -3- methyl-isoindolin-1-one; 6- chloro-2- [5- [2- (1-methylpirazol-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -3,4-dihydroisoquinolin-1 -one; (3R or 3S) -5-doro-3-methyl-2- [4-methyl-5- [2- (1-methylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1-one; (3S or 3R) -5-doro-3-methyl-2- [4-methyl-5- [2- (1-methylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1-one; 5-doro-3,3-dimethyl-2- [5- [7- (1-methylpyrazole-4-carbonyl) -2,7-diazaspi ro [3.5] nonan-2-yl] -3-pyridyl] isoindolin- 1-one; 5-doro-3,3-dimethyl-2- [5- [7- (4-methylpyridine-3-carbonyl) -2,7-diazaspiro [3.5] nonan-2-yl] -3-pyridyl] isoindolin-1 -one; 5-doro-2- [5- [7- (1-ethylpyrazole-4-carbonyl) -2,7-diazaspiro [3.5] nonan-2-yl] -3-pyridyl] -3,3-dimethyl-isoindolin- 1-one; 5-doro-3,3-dimethyl-2- [5- [2- (1-methylpyrazole-4-carbonyl) -2,7-diazaspiro [3.5] nonan-7-yl] -3-pyridyl] isoindolin-1 -one; 5-doro-2- [5- [2- (1-ethylpyrazole-4-carbonyl) -2,7-diazaspiro [3.5] nonan-7-yl] -3-pyridyl] -3,3-dimethyl-isoindolin- 1-one; 5-doro-3,3-dimethyl-2- [5- [2- (4-methylpyridine-3-carbonyl) -2,7-diazaspiro [3.5] nonan-7-yl] -3-pyridyl] isoindolin-1 -one; and pharmaceutically acceptable salts thereof. 10. A compound according to any one of claims 1 to 9, selected from 5-doro-3,3-dimethyl-2- [5- [2- (1-methylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1 -one; 5-chloro-2- [5- [2- (1-ethylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -3,3-dimethyl-isoindolin- 1-one; 5-chloro-3,3-dimethyl-2- [5- [2- (4-methylpyridine-3-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] isoindolin-1 -one; 2- [5- [2- (1-Ethylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] -3,3-dimethyl-1-oxo-isoindoline- 5-carbonitrile; 2-methoxy-7,7-dimethyl-6- [5- [2- (1-methylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] pyrrolo [3 , 4-b] pyridin-5-one; 5'-chloro-2 '- [5- [2- (1-methylpyrazole-4-carbonyl) -2,6-diazaspiro [3.3] heptan-6-yl] -3-pyridyl] spiro [cyclopropane-1,3 '-isoindolin] -1'-one; 5-chloro-3,3-dimethyl-2- [5- [7- (1-methylpyrazole-4-carbonyl) -2,7-diazaspiro [3.5] nonan-2-yl] -3-pyridyl] isoindolin-1 -one; 5-chloro-2- [5- [7- (1-ethylpyrazole-4-carbonyl) -2,7-diazaspiro [3.5] nonan-2-yl] -3-pyridyl] -3,3-dimethyl-isoindolin- 1-one; 5-chloro-3,3-dimethyl-2- [5- [2- (1-methylpyrazole-4-carbonyl) -2,7-diazaspiro [3.5] nonan-7-yl] -3-pyridyl] isoindolin-1 -one; and pharmaceutically acceptable salts thereof. 11. A process for preparing a compound according to any one of claims 1 to 10, comprising a) the reaction of a compound of formula (II) in the presence of a compound of formula (III);

or b) reacting a compound of formula (IV) in the presence of a compound of formula (V);

wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, A1, A2 m, n and p are as described in any one of claims 1 a 8 and X in step a) is halogen or triflate and is halogen in step b). 12. A compound according to any one of claims 1 to 10 for use as a therapeutically active substance. 13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 and a therapeutically inert carrier. 14. A compound according to any one of claims 1 to 10 for use in the treatment or prophylaxis of chronic renal failure, congestive heart failure, hypertension, primary hyperaldosteronism and Cushing's syndrome.